DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Clonidine (known by the trade names Catapres, Kapvay, Nexiclon, Clophelin, and others) is a depressant substance of the imidazoline class. It is primarily used to treat high blood pressure, but can also be used for a variety of conditions that include attention deficit hyperactivity disorder, anxiety disorders, tic disorders, substance withdrawal, migraine, diarrhea, and certain pain conditions.[1]

Developed by Boehringer Ingelheim for its blood pressure effects, clonidine first saw clinical use in 1966.[2]
As the first anti-hypertensive agent with a clearly identifiable central site of action, clonidine has been an important pharmacological tool in discovering the role of central α-adrenoceptors in the physiology of central blood pressure regulation.[2]

Clonidine has several off-label uses. It has been prescribed to treat psychiatric disorders including stress, sleep disorders, and hyperarousal caused by post-traumatic stress disorder, borderline personality disorder, and other anxiety disorders.[5][6][7][8][9][10][11][12]

History and culture

In the early 1960s, the medicinal chemist Helmut Stähle was tasked by Boehringer Ingelheim with synthesizing a peripherally active a-adrenergic compound that would be useful for nasal decongestion as simple nose drops. A locally acting a-adrenergic vasoconstrictor agent was expected to provide relief from the symptoms of the common cold by shrinking the swollen nasal membranes and producing an unobstructed air passage.[2]

The synthetic design of clonidine was achieved when Stähle had the idea of substituting two chlorine groups on the phenyl group of the imidazoline structure, which most of the newer decongestive agents at the time were derived from. At that time, a double halogen substitution was still unusual for pharmaceuticals, and the prevailing opinion was that compounds with several halogen atoms would at best be useful as pesticides. Despite this, clonidine was pursued and discovered to have a remarkably high vasoconstrictive and decongestive effect at an unusually low dosage level.[2]

The decongestive effects were then determined by nasal cavity tests on anesthetized dogs. After the first trial in humans, it became clear that clonidine's decongestant properties were far less interesting than its potent anti-hypertensive effects. The compound was then developed for this new indication and was introduced into therapy in 1966 under the trade name Catapres, where it saw widespread use.[2]

With the discovery of clonidine, the central a-adrenergic receptors first became known to chemists, pharmacologists and physicians. It has been an important pharmacological tool in researching the role of central α-adrenoceptors in the physiology of central blood pressure regulation and nervous system function.[2]

In the 2010s, the US Food and Drug Administration (FDA) approved clonidine, both alone or with stimulants, for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric and adult patients. In Australia, clonidine is an accepted but not approved use for ADHD by the TGA.[13]

Chemistry

Clonidine, or 2-[(2,6-Dichlorophenyl)imino]imidazoline, is a compound of the imidazoline chemical class. Imidazolines are substituted amidines in which the amidine function is incorporated into an imidazoline ring. This portion is connected to an aromatic nucleus by way of a methylene bridge.

Additionally, two chlorine atoms are substituted in the 2- and 6-positions of the phenyl ring. This addition has the critical effect of making the molecule sufficiently lipophilic to penetrate the blood-brain barrier.[citation needed]

Other compounds of this class include the a-adrenergic agents tolazoline, naphazoline, and phentolamine. The a-adrenergic effects of clonidine and other imidazolidine compounds may be explained on the basis of a structural overlap between clonidine and norepinephrine.

Pharmacology

Pharmacodynamics

Clonidine is an agonist for the α2adrenergicreceptor. When α2 receptors in the brain are stimulated, peripheral vascular resistance decreases, resulting in lowered blood pressure. It has specificity towards the presynaptic α2 receptors in the vasomotor center in the brainstem. This binding decreases presynaptic calcium levels and inhibits the release of norepinephrine (NE). The net effect is a decrease in sympathetic nervous system tone.[14]

Three G-protein coupled α2-receptor subtypes have been identified: α2A, α2B, and α2C. Each subtype has a unique pattern of tissue distribution in the central nervous system and peripheral tissues. The α2A-receptor is widely distributed throughout the central nervous system; it is found in the locus coeruleus, brain stem nuclei, cerebral cortex, septum, hypothalamus, and hippocampus. α2A receptors are also expressed in the kidneys, spleen, thymus, lung and salivary glands. The α2C-receptor is primarily expressed in the central nervous system, including the striatum, olfactory tubercle, hippocampus and cerebral cortex. The α2B receptor is located primarily in the periphery (kidney, liver, lung and heart).[citation needed]

The α2A- and α2C receptors are located presynaptically and inhibit the released of noradrenaline from sympathetic nerves. Stimulation of these receptors decreases sympathetic tone, resulting in decreases in blood pressure and heart rate. Sedation and analgesia is mediated by centrally located α2A receptors, while peripheral α2B receptors mediate constriction of vascular smooth muscle. α2A receptors also mediate essential components of the analgesic effect of nitrous oxide in the spinal cord. Clonidine stimulates all three α2 receptor subtypes with similar potency.[citation needed]

Pharmacokinetics

Clonidine is rapidly absorbed from the gastrointestinal tract and has excellent CNS penetration because of lipid solubility.[citation needed] Peak plasma concentrations are reached 3-5 hours after a single oral dose.[citation needed] No known pharmacologically active metabolites exist.[citation needed] Plasma half-life is 12-16 hours, with the antihypertensive effects occurring within 30-60 minutes of ingestion. Clonidine is excreted unchanged in the urine and is metabolized by the liver.[citation needed]

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWikicontributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects

Sedation - Clonidine can produce a strong sedative effect, which has been compared to that of benzodiazepines. Users can become very tired and sleep through prompts to awake.

Decreased heart rate[18] - In normal use as well as overdose, heartrate is lowered and is directly affected by how much is taken.

Abnormal heartbeat - This effect has a low likelihood. Caution should be taken if clonidine is taken with other substances that affect heartbeat. Intense physical activity should be avoided while on this substance.

Cognitive effects

Addiction suppression - Clonidine has shown efficacy as a treatment for alcohol, opioid, and nicotine substance use disorders.[citation needed] It has been shown to block opiate withdrawal symptoms.[20]

Anxiety suppression - Clonidine has mild to moderate anxiolytic effects and is sometimes used clinically to treat anxiety.[21]

Focus enhancement - This effect usually occurs at lower doses which are sometimes prescribed for the treatment of ADHD.

Auditory effects

Auditory suppression - Reports describe this effect as a "hollow" loss of hearing. It is believed to be a result of lowered blood pressure.

After effects

Irritability - One can feel very agitated and annoyed, especially with more ease. This especially happens when the medicine is suddenly stopped, which is an incorrect practice; clonidine should be tapered off of the user.

Increased heart rate - This occurs as a rebound effect to clonidine's antihypertensive effects and is typically only prominent following sustained use.

Increased blood pressure - This occurs as a rebound effect to clonidine's antihypertensive effects and is typically only prominent following sustained use.

Experience reports

There are currently 1 anecdotal reports which describe the effects of this compound within our experience index.

Toxicity and harm potential

At therapeutic doses (0.2-0.9 mg/d), clonidine is commonly associated with adverse effects such as dry mouth, sedation, dizziness, and constipation. While generally safe, at toxic doses clonidine can cause serious cardiopulmonary instability and central nervous system (CNS) depression in children and adults. Caution should be used when clonidine is taken with other depressants.

Lethal dosage

The oral LD50 for clonidine in mice is 206 mg/kg and for rats, 465 mg/kg.[citation needed] In humans, lethality is rare with a small number of reported deaths. Morbidity, in terms of cardiorespiratory and CNS dysfunction, generally tends to be more severe in young persons than in adults.[citation needed]

Overdose

Symptoms of clonidine overdose include constriction of pupils of the eye, drowsiness, high blood pressure followed by a drop in pressure, irritability, low body temperature, slowed breathing, slowed heartbeat, slowed reflexes, and weakness.[citation needed]

There are case reports that show naloxone may be a useful antidote in treating clonidine overdoses. However, this is not in widespread clinical use.[22]

Tolerance and addiction potential

Clonidine is not addictive and has a low potential for abuse. The chronic use of clonidine can produce physical dependence and withdrawal symptoms if one suddenly stops their usage. Clonidine therapy should generally be gradually tapered when discontinuing therapy to avoid rebound hypertension from occurring.

Although clonidine is not considered to be addictive, cases of misuse have been documented among certain groups with pre-existing substance use disorders. It is sometimes used in combination with opiates to extend and potentiate their effects.[23] This practice may increase the risk of oversedation and respiratory depression associated with opioid use.

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can quickly become harmful and even life-threatening when taken with other substances. The following section lists some known dangerous combinations, but it may not include all of them. Furthermore, a combination that seems to be harmless in low doses can still greatly increase the risk of injury or death when the doses are slightly increased. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume. Some interactions listed have been sourced from Tripsit.

Stimulants - It can be dangerous to combine depressants with stimulants due to the risk of accidental excessive intoxication. Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states. This combination can also potentially result in severe dehydration if one's fluid intake is not closely monitored. If choosing to combine these substances, one should strictly limit themselves to a pre-set schedule of dosing only a certain amount per hour until a maximum threshold has been reached.

↑Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 25 November 2013.